Process for the preparation of 4-methylenepiperidine

ABSTRACT

A process for preparing 4-methylenepiperidine having a formula (VII): ##STR1## which comprises reacting an isonipecotate having a formula (I): ##STR2## wherein R 1  is methyl group or ethyl group, with an acylating agent having a formula (II): R 2  X or a formula (II&#39;): (R 2 ) 2  O wherein R 2  is benzoyl group or acetyl group and X is chlorine atom or bromine atom, in the presence or the absence of a base, reducing the resulting ester having a formula (III): ##STR3## wherein R 1  and R 2  are the same as defined above, with sodium borohydride or lithium borohydride in an organic solvent containing methanol, reacting the resulting alcohol with a halogenating agent without any solvent or in an organic solvent in the presence or the absence of a base, reacting the resulting halide with a dehydrohalogenating agent in an organic solvent and hydrolyzing the resulting methylene compound having a formula (VI): ##STR4## wherein R 2  is the same as defined above, with a strong alkaline in water or an organic solvent containing water.

TECHNICAL FIELDS

The present invention relates to a process for preparing4-methylenepiperidine which is an intermediate for the synthesis of acompound having a formula (VIII): ##STR5## (a compound described inExample 1 in the published International Application No. WO94/26734(1994)) known to be useful as a fungicide.

BACKGROUND ART

As a process for synthesizing 4-methylenepiperidine, there have beenknown the method wherein an aqueous solution of 4-bromoquinuclidine isheated (P. Brenneisen et al., Helv. Chim. Acta, 48(1), 146-156(1965))and the method wherein N-benzyl-4-piperidone is reacted with a Wittigreagent and then debenzylation is carried out to obtain4-methylenepiperidine (M. Mimura et al., Chem. Pharm. Bull., 41(11),1971-1986(1993)). However, by either of these methods, it is difficultto manufacture a large amount of 4-methylenepiperidine at low costbecause of the difficulty of obtaining the starting material or the useof an expensive reagent such as the Wittig reagent.

The object of the present invention is to provide a process forpreparing 4-methylenepiperidine efficiently in short process from acheap starting material which is obtainable at large amount.

DISCLOSURE OF THE INVENTION

As the result of the continuous effort and detailed investigation of thepresent inventors to achieve the above-mentioned object, they have founda process for preparing 4-methylenepiperidine at low cost wherein astarting material is an isonipecotate which is easily obtainable at lowprice.

The present invention relates to

a process for preparing a methylene compound having a formula (VI):##STR6## wherein R² is benzoyl group or acetyl group, which comprisesreacting a halide having a formula (V): ##STR7## wherein X is chlorineatom or bromine atom and R² is the same as defined above, with adehydrohalogenating agent in an organic solvent,

a process for preparing an alcohol having a formula (IV): ##STR8##wherein R² is benzoyl group or acetyl group, which comprises reducing anester having a formula (III): ##STR9## wherein R¹ is methyl group orethyl group and R2 is the same as defined above, with sodium borohydrideor lithium borohydride in an organic solvent containing methanol,

a process for preparing a halide having a formula (V): ##STR10## whereinX is chlorine atom or bromine atom and R² is benzoyl group or acetylgroup, which comprises reacting an alcohol having a formula (IV):##STR11## wherein R² is the same as defined above, with a halogenatingagent without any solvent or in an organic solvent in the presence orthe absence of a base,

a process for preparing a methylene compound having a formula (VI):##STR12## wherein R² is benzoyl group or acetyl group, which comprisesreducing an ester having a formula (III): ##STR13## wherein R¹ is methylgroup or ethyl group and R² is the same as defined above, with sodiumborohydride or lithium borohydride in an organic solvent containingmethanol, reacting a resulting alcohol having a formula (IV): ##STR14##wherein R² is the same as defined above, with a halogenating agentwithout any solvent or in an organic solvent in the presence or theabsence of a base and reacting a resulting halide having a formula (V):##STR15## wherein X is chlorine atom or bromine atom and R² is the sameas defined above, with a dehydrohalogenating agent in an organicsolvent,

a process for preparing an ester having a formula (III): ##STR16##wherein R¹ is methyl group or ethyl group and R² is benzoyl group oracetyl group, which comprises reacting an isonipecotate having a formula(I): ##STR17## wherein R¹ is the same as defined above, with anacylating agent having a formula (II): R² X or a formula (II'): (R²)₂ Owherein R² is the same as defined above and X is chlorine atom orbromine atom, in the presence or the absence of a base,

a process for preparing 4-methylenepiperidine having a formula (VII):##STR18## which comprises hydrolyzing a methylene compound having aformula (VI): ##STR19## wherein R² is benzoyl group or acetyl group,with a strong alkaline in water or an organic solvent containing water,and

a process for preparing 4-methylenepiperidine having a formula (VII):##STR20## which comprises reacting an isonipecotiate having a formula(I): ##STR21## wherein R¹ is methyl group or ethyl group, with anacylating agent having a formula (II): R² X or a formula (II'): (R²)₂ Owherein R² is benzoyl group or acetyl group and X is chlorine atom orbromine atom, in the presence or the absence of a base, reducing aresulting ester having a formula (III): ##STR22## wherein R¹ and R² arethe same as defined above, with sodium borohydride or lithiumborohydride in an organic solvent containing methanol, reacting aresulting alcohol having a formula (IV): ##STR23## wherein R² is thesame as defined above, with a halogenating agent without any solvent orin an organic solvent in the presence or the absence of a base, reactinga resulting halide having a formula (V): ##STR24## wherein X and R² arethe same as defined above, with a dehydrohalogenating agent in anorganic solvent and hydrolyzing a resulting methylene compound having aformula (VI): ##STR25## wherein R² is the same as defined above, with astrong alkaline in water or an organic solvent containing water.

BEST MODE FOR CARRYING OUT THE INVENTION

The processes of the present invention are explained below according tothe stages. Each stage in the present invention can be carried out usingthe starting compound at any amount ranging from the g-level to the 100kg-level, and the amount of the solvent can be determined according tothe amount of the starting compound to be used.

An isonipecotate having the formula (I): ##STR26## wherein R¹ is methylgroup or ethyl group, is reacted with an acylating agent having theformula (II): R² X or the formula (II'): (R²)₂ O, wherein R² is benzoylgroup or acetyl group and X is chlorine atom or bromine atom, in thepresence or the absence of a base to obtain an ester having the formula(III): ##STR27## wherein R¹ and R² are the same as defined above.

As the isonipecotate, a commercially available one can be used and it isavailable from, for instance, TOKYO KASEI KOGYO Co., Ltd. Preferableacylating agents (II) used in the reaction are benzoyl chloride andacetyl chloride as an acyl halide and acetic anhydride and benzoicanhydride as an acid anhydride. Particularly, benzoyl chloride ispreferable from the viewpoint of that it is obtainable at low price andit is easy to purify the produced material. The amount of the acylatingagent (II) is from 1 to 2 molar equivalents, preferably from 1 to molarequivalents, based on the isonipecotate (I).

In the case of using the base, there can be used an organic base such aspyridine, triethylamine or morpholine or an inorganic base such assodium hydroxide, potassium hydroxide, sodium carbonate, potassiumcarbonate or sodium hydrogencarbonate. The amount of the base is fromthe same amount to the excessive amount, preferably from 1 to 1.5 molarequivalents, based on the isonipecotate (I).

The reaction is carried out using or not using a solvent. Examples ofthe solvent are hydrocarbons such as toluene, xylene, benzene andhexane, esters such as ethyl acetate and butyl acetate, amides such asN,N-dimethylformamide and N,N-dimethylacetoamide, ethers such asdioxane, tetrahydrofuran and diisopropyl ether, halogenated hydrocarbonssuch as dichloromethane, 1,2-dichloroethane and chloroform, a mixture ofat least two kinds of the above-mentioned solvents, and a mixed solventof water and at least one kind of the above-mentioned solvents.

The reaction is carried out at the reaction temperature of from -20° to100° C., with cooling, at room temperature or, if necessary, withheating. The reaction time is from 1 to 24 hours. The reaction can becarried out under any pressure and, usually, is carried out atatmospheric pressure. The produced compound may be purified according tothe usual method.

Then, the ester (III) is reduced with sodium borohydride or lithiumborohydride in an organic solvent containing methanol to obtain analcohol having the formula (IV): ##STR28## wherein R² is the same asdefined above.

The amount of sodium borohydride or lithium borohydride is from 1 to 2molar equivalents based on the ester (III). The amount of methanol isfrom 1 to 3 molar equivalents, preferably 3 molar equivalents based onsodium borohydride or lithium borohydride. Examples of the organicsolvent used are ethers such as dioxane and tetrahydrofuran, tertiaryalcohols such as tert-butanol, and amides such as N,N-dimethylformamideand N,N-dimethylacetoamide. The ratio of methanol and the organicsolvent is from 1:3 to 1:10 (v/v).

To a reaction mixture which is obtained by adding the ester (III) andsodium borohydride or lithium borohydride to the organic solvent,methanol is added over 2 to 6 hours with cooling at 0° to 30° C. Afterthe generation of hydrogen gas becomes weak, the reaction mixtureundergoes a reaction with stirring, with cooling at 0° to 20° C. for 0.5to 2 hours and then at room temperature for 1 hour to overnight. Lastlythe reaction mixture undergoes a reaction at 40° to 60° C. for 1 to 6hours with stirring in order to complete the reaction. The reaction canbe carried out under any pressure and, usually, is carried out atatmospheric pressure.

The reaction can be also carried out in the same way even if a loweralcohol such as ethanol or propanol is substituted for methanol in theabove-mentioned reaction. The produced compound may be purifiedaccording to the usual method.

Then, the alcohol (IV) is reacted with a halogenating agent without anysolvent or in an organic solvent in the presence or the absence of abase to obtain a halide having the formula (V): ##STR29## wherein X andR² are the same as defined above.

Examples of the halogenating agent are, for instance, thionyl chloride,phosphorus pentachloride, phosphorus tribromide, phosphorus oxychlorideand the like. Particularly, the method wherein thionyl chloride is usedwithout adding a base is suitable because the treatment after thereaction can be carried out easily. The amount of the halogenating agentis from 1 to 2 molar equivalents, preferably from 1 to 1.5 molarequivalents, based on the alcohol (IV). In the case of using a base, anorganic amine such as pyridine or triethylamine is used.

Examples of the organic solvent to be used are aromatic solvents such astoluene, xylene, benzene and chlorobenzene, halogenated hydrocarbonssuch as dichloromethane, 1,2-dichloroethane and chloroform, andhydrocarbons such as n-hexane and cyclohexane.

The reaction temperature is suitably determined within the range from 0°C. to the boiling point of the solvent used. The reaction time is from 1to 24 hours. The reaction can be carried out under any pressure and,usually, is carried out at atmospheric pressure. The produced compoundmay be purified according to the usual method.

Then, the halide (V) is reacted with a dehydrohalogenating agent in anorganic solvent to obtain a methylene compound having the formula (VI):##STR30## wherein R² is the same as defined above.

The dehydrohalogenating agent is preferably an alkali metal alkoxidesuch as potassium tert-butoxide, sodium tert-butoxide, sodium methoxideor sodium ethoxide because it has high reactivity and is obtainable atlow price. The amount of the dehydrohalogenating agent is from 1 to 5molar equivalents, preferably from 1 to 4 molar equivalents, based onthe halide (V).

The organic solvent to be used is preferably N,N-dimethylformamide,N,N-dimethylacetoamide and dimethylsulfoxide. The reaction time is from0.5 to 24 hours, preferably from 0.5 to 5 hours. The reactiontemperature is from -10° to 100° C., preferably from 0° to 60° C. Thereaction can be carried out under any pressure and, usually, is carriedout at atmospheric pressure. The produced compound may be purifiedaccording to the usual method.

Thereafter, the methylene compound (VI) is hydrolyzed with a strongalkali in water or an organic solvent containing water to obtain4-methylenepiperidine having the formula (VII): ##STR31##

Examples of the strong alkali to be used are sodium hydroxide, potassiumhydroxide and the like. The amount of the strong alkali is from 1 to 3molar equivalents based on the methylene compound (VI). The organicsolvent to be used is preferably an alcohol having a high boiling pointsuch as ethylene glycol or propylene glycol. The ratio of water and theorganic solvent is from 1:20 to 1:1 (v/v).

The reaction temperature is from 80° to 150° C. The reaction time isfrom 1 to 6 hours. After the reaction, 4-methylenepiperidine is isolatedfrom the reaction mixture by distillation under atmospheric pressure orreduced pressure. The reaction can be carried out under any pressureand, usually, is carried out at atmospheric pressure. The producedcompound may be purified according to the usual method.

Thus obtained 4-methylenepiperidine usually has a water content of 20%to 70% by weight. As occasion demands, 4-methylenepiperidine having awater content of at most 20% by weight or anhydrous4-methylenepiperidine can be also obtained by adding cyclohexane andsubjecting the mixture to azeotropic dehydration. Further, a saltthereof with an acid can be also obtained if, for example, the obtained4-methylenepiperidine is neutralized by adding an acid such ashydrochloric acid or sulfuric acid and then water is removed bydistillation

In the followings, the processes of the present invention are concretelyexplained by means of Examples, however, it is not to be understood thatthe present invention is limited to the Examples. The "%" described inthe followings means "% by weight" unless otherwise noted. The reactionswere carried out under atmospheric pressure.

EXAMPLE 1 ##STR32## Synthesis of ethyl N-benzoylisonipecotate (B)

To 157.21 g (1 mol) of ethyl isonipecotate (A) were added 79.10 g (1mol) of pyridine and 1 l of toluene. After cooling the mixture to 9° C.,thereto was added dropwise 147.6 g (1.05 mol) of benzoyl chloride at 10°to 20° C. over 30 minutes with cooling. The reaction mixture was furtherstirred with cooling with ice for 1 hour and at room temperature for 1hour. Then, thereto was added 500 ml of water to separate an organiclayer. The organic layer was washed with 100 ml of water and 200 ml of a5% aqueous solution of sodium hydrogencarbonate, succesively. Then,thereto was added 10 g of anhydrous magnesium sulfate. After drying, thesolvent was removed by distillation to obtain 262.48 g of ethylN-benzoylisonipecotate (B). The NMR spectrum of the obtained compoundwas measured. The result is shown below.

NMR(CDCl₃)δ: 1.27(3H,t,J=7.2 Hz), 1.5-2.2(4H,br), 2.5-2.65(1H,m),2.9-3.2(2H,br), 3.6-3.9(1H,br), 4.16(2H,q,J=7.2 Hz), 4.4-4.7(1H,br),7.40(5H,m)

EXAMPLE 2 ##STR33## Synthesis of N-benzoyl-4-hydroxymethylpiperidine (C)

To 261.48 g (1 mol) of ethyl N-benzoylisonipecotate (B) obtained inExample 1 was added 800 ml of dioxane and the compound (B) wasdissolved. The solution was cooled to 8° C. Thereto was added 75.67 g (2mol) of sodium borohydride with cooling and, then, added dropwise 243 mlof methanol at 15° to 18° C. over 2 hours with cooling, keeping thereaction mixture not overflowing due to the foaming. The reactionmixture was stirred with cooling at not more than 20° C. for 0.5 hourand at room temperature overnight. Thereafter, the mixture was heated at45° C. for 6 hours with stirring. After the completion of the reaction,the reaction mixture was cooled down to room temperature and thereto wasadded 700 ml of iced water and then the mixture was neutralized with 3Nhydrochloric acid (400 ml was required). Then, dioxane was removed bydistillation under reduced pressure and to the residue were added 200 mlof water and 300 ml of dichloromethane to separate an organic layer. Theaqueous layer was extracted twice with 100 ml of dichloromethane. Theorganic layers were combined and dried over 10 g of anhydrous magnesiumsulfate to obtain about 800 ml of a dichloromethane solution containingabout 1 mol of N-benzoyl-4-hydroxymethylpiperidine (C). This solutionwas used in the subsequent stage (Example 3) as it was. A portion of thesolution was gathered separately and, after removing the solvent bydistillation, the NMR spectrum was measured. The result is shown below.NMR(CDCl₃)δ: 1.05-1.35(2H,br), 1.6-1.9(3H,br), 2.5(1H,brs),2.65-3.1(2H,br), 3.4-3.5(2H,m), 3.65-3.85(1H,br), 4.6-4.9(1H,br),7.4(5H,m)

EXAMPLE 3 ##STR34## Synthesis of N-benzoyl-4-chloromethylpiperidine (D)

To 800 ml of the dichloromethane solution ofN-benzoyl-4-hydroxymethylpiperidine (C) obtained in Example 2, whichcontains about 1 mol of N-benzoyl-4-hydroxymethylpiperidine, there wasadded dropwise 109 ml (1.5 mol) of thionyl chloride over 2 hours withkeeping the reaction temperature at 25° to 30° C. Then the obtainedreaction mixture was stirred at room temperature for 1 hour and at 35°C. for 8 hours. After the completion of the reaction, the solvent andthe excess of thionyl chloride were removed by distillation to obtain248.96 g of N-benzoyl-4-chloromethylpiperidine (D) as a yellowish brownoily matter. The NMR spectrum of the obtained compound was measured. Theresult is shown below.

NMR(CDCl₃)δ: 1.15-1.5(2H,br), 1.7-2.05(3H,br), 2.65-3.15(2H,br),3.4-3.5(2H,m), 3.7-4.0(1H,br), 4.7-5.0(1H,br), 7.4(5H,m)

EXAMPLE 4 ##STR35## Synthesis of N-benzoyl-4-methylenepiperidine (E)

In 1 l of N,N-dimethylformamide was dissolved 248.96 g (about 1 mol) ofN-benzoyl-4-chloromethyl-piperidine (D) obtained in Example 3. Theresulting solution was cooled to 5° C. and thereto was added 168.32 g(1.5 mol) of potassium tert-butoxide in five portions at 10° to 20° C.over about 1 hour. After the addition, the mixture was stirred at 10° to20° C. for 40 minutes. Then, the reaction mixture was poured into amixed liquid of 500 ml of 1N hydrochloric acid and 500 g of fragmentaryice. Subsequently, thereto was added 200 ml of toluene to separate anorganic layer. The aqueous layer was extracted with 200 ml of tolueneand the organic layers were combined. The combined organic layer waswashed with 500 ml of water. The solvent was removed by distillationunder reduced pressure to obtain 193.78 g ofN-benzoyl-4-methylenepiperidine (E) as a yellowish brown oily matter.The NMR spectrum of the obtained compound was measured. The result isshown below.

NMR(CDCl₃)δ: 2.1-2.45(4H,br), 3.3-3.55(2H,br), 3.65-3.9(2H,br),4.80(2H,s), 7.4(5H,m),

EXAMPLE 5 ##STR36## Synthesis of 4-methylenepiperidine (F)

To 193.78 g (about 1 mol) of N-benzoyl-4-methylenepiperidine (E)obtained in Example 4 were added 300 ml of ethylene glycol, 84.17 g (1.5mol) of potassium hydroxide and 30 ml of water. The resulting mixturewas heated at 110° C. for 2 hours with stirring. After the completion ofthe reaction, thereto was added 170 ml of water. After cooling down toroom temperature, thereto was added 150 ml of toluene and the mixturewas adjusted to pH 3 with concentrated hydrochloric acid (186 ml wasrequired). The deposited crystal of benzoic acid was separated byfiltration. The obtained filtrate was adjusted to pH 4 with a 1N aqueoussolution of sodium hydroxide and then water was removed by distillationunder reduced pressure. Thereafter, to the residual liquid was added 56g (1 mol) of potassium hydroxide and the distillation was carried out.The fraction distilled at the boiling point of 97° to 110° C. wascollected to obtain 118 g of 4-methylenepiperidine (F). In thisdistillate, 63% anhydrous 4-methylenepiperidine was contained(calculated by the titration with 0.1 N HCl). The total yield from theisonipecotic acid ethyl ester (A) in Example 1 was 76%. The NMR spectrumof the obtained compound was measured. The result is shown below.

NMR(CDCl₃)δ: 2.18(4H,t,J=5.61), 2.86(4H,t,J=5.61), 4.81(2H,s)

EXAMPLE 6 ##STR37## Synthesis of N-benzoyl-4-chloromethylpiperidine (D)

In 10 ml of chloroform was dissolved 2.19 g (10 mmol) ofN-benzoyl-4-hydroxymethylpiperidine (C) and to the resulting solutionwere added 0.81 ml (10 mmol) of pyridine and 1.4 ml (15 mmol) ofphosphorus oxychloride. The resulting mixture was stirred at roomtemperature for 24 hours. After the completion of the reaction, theretowas added 10 ml of chloroform and the resulting mixture was poured into20 ml of iced water to separate an organic layer. The organic layer waswashed with 20 ml of water and dried over 3 g of anhydrous magnesiumsulfate. Then, the solvent was removed by distillation to obtain 3.18 gof an oily matter. The oily matter was subjected to silica gel columnchromatography (stationary phase: 40 g of Silicagel 60 available fromMerck KGaA). The fraction eluted with a hexane/ethyl acetate mixture(1:1 (v/v)) was collected. The solvent was removed by distillation fromthe obtained fraction to obtain 1.27 g ofN-benzoyl-4-chloromethylpiperidine (D) as a colorless crystal. The NMRspectrum of this compound coincided with that of the product in Example3.

EXAMPLE 7 ##STR38## Synthesis of N-benzoyl-4-chloromethylpiperidine (D)

In 20 ml of chloroform was dissolved 2.19 g (10 mmol) ofN-benzoyl-4-hydroxymethylpiperidine (C) and to the resulting solutionwas added 2.08 g (10 mmol) of phosphorus pentachloride. The resultingmixture was stirred at room temperature for 1 hour. After the completionof the reaction, thereto was added 20 ml of chloroform and the resultingmixture was poured into 50 ml of iced water to separate an organiclayer. The organic layer was washed with 50 ml of a saturated aqueoussolution of sodium hydrogencarbonate and dried over 4 g of anhydrousmagnesium sulfate. Then, the solvent was removed by distillation toobtain 3.03 g of an oily matter. The oily matter was subjected to silicagel column chromatography (stationary phase: 50 g of Silicagel 60available from Merck KGaA). The fraction eluted with a hexane/ethylacetate mixture (1:1 (v/v)) was collected. The solvent was removed bydistillation from the obtained fraction to obtain 1.33 g ofN-benzoyl-4-chloromethylpiperidine (D) as a colorless crystal. The NMRspectrum of this compound coincided with that of the product in Example3.

EXAMPLE 8 ##STR39## Synthesis of N-benzoyl-4-methylenepiperidine (E)

In 10 ml of N,N-dimethylformamide was dissolved 1.50 g (6.32 mmol) ofN-benzoyl-4-chloromethylpiperidine (D). The resulting solution wascooled to 5° C. and thereto was added 1.36 g (25.28 mmol) of sodiummethoxide. After stirring at 60° C. for 4 hours, the reaction mixturewas cooled down to room temperature and then poured into a mixed liquidof 40 ml of toluene and 40 ml of iced water. An organic layer wasseparated and dried over 2 g of anhydrous magnesium sulfate and,thereafter, the solvent was removed by distillation. The residual liquidwas subjected to silicagel column chromatography (stationary phase: 50 gof Silicagel 60 available from Merck KGaA). The fraction eluted with ahexane/ethyl acetate mixture (2:1 (v/v)) was collected. The solvent wasremoved by distillation from the obtained fraction to obtain 1.00 g ofN-benzoyl-4-methylenepiperidine (E) as a colorless crystal. The NMRspectrum of this compound coincided with that of the product in Example4.

INDUSTRIAL APPLICABILITY

According to the present invention, 4-methylenepiperidine, anintermediate for synthesizing a fungicide, can be efficiently preparedat low cost in short process.

I claim:
 1. A process for preparing a methylene compound having aformula (VI): ##STR40## wherein R² is benzoyl group or acetyl group,which comprises reacting a halide having a formula (V): ##STR41##wherein X is chlorine atom or bromine atom and R² is the same as definedabove, with a dehydrohalogenating agent in an organic solvent.
 2. Aprocess for preparing an alcohol having a formula (IV): ##STR42##wherein R² is benzoyl group or acetyl group, which comprises reducing anester having a formula (III): ##STR43## wherein R¹ is methyl group orethyl group and R² is the same as defined above, with sodium borohydrideor lithium borohydride in an organic solvent containing methanol.
 3. Aprocess for preparing a halide having a formula (V): ##STR44## wherein Xis chlorine atom or bromine atom and R² is benzoyl group or acetylgroup, which comprises reacting an alcohol having a formula (IV):##STR45## wherein R² is the same as defined above, with a halogenatingagent without any solvent or in an organic solvent in the presence orthe absence of a base.
 4. A process for preparing a methylene compoundhaving a formula (VI): ##STR46## wherein R² is benzoyl group or acetylgroup, which comprises reducing an ester having a formula (III):##STR47## wherein R¹ is methyl group or ethyl group and R² is the sameas defined above, with sodium borohydride or lithium borohydride in anorganic solvent containing methanol, reacting a resulting alcohol havinga formula (IV): ##STR48## wherein R² is the same as defined above, witha halogenating agent without any solvent or in an organic solvent in thepresence or the absence of a base and reacting a resulting halide havinga formula (V): ##STR49## wherein X is chlorine atom or bromine atom andR² is the same as defined above, with a dehydrohalogenating agent in anorganic solvent.
 5. A process for preparing an ester having a formula(III): ##STR50## wherein R¹ is methyl group or ethyl group and R² isbenzoyl group or acetyl group, which comprises reacting an isonipecotatehaving a formula (I): ##STR51## wherein R¹ is the same as defined above,with an acylating agent having a formula (II): R² X or a formula (II'):(R²)₂ O wherein R² is the same as defined above and X is chlorine atomor bromine atom, in the presence or the absence of a base.
 6. A processfor preparing 4-methylenepiperidine having a formula (VII): ##STR52##which comprises hydrolyzing a methylene compound having a formula (VI):##STR53## wherein R² is benzoyl group or acetyl group, with a strongalkali in water or an organic solvent containing water.
 7. A process forpreparing 4-methylenepiperidine having a formula (VII): ##STR54## whichcomprises reacting an isonipecotate having a formula (I): ##STR55##wherein R¹ is methyl group or ethyl group, with an acylating agenthaving a formula (II): R² X or a formula (II'): (R²)₂ O wherein R² isbenzoyl group or acetyl group and X is chlorine atom or bromine atom, inthe presence or the absence of a base, reducing a resulting ester havinga formula (III): ##STR56## wherein R¹ and R² are the same as definedabove, with sodium borohydride or lithium borohydride in an organicsolvent containing methanol, reacting a resulting alcohol having aformula (IV): ##STR57## wherein R² is the same as defined above, with ahalogenating agent without any solvent or in an organic solvent in thepresence or the absence of a base, reacting a resulting halide having aformula (V): ##STR58## wherein X and R² are the same as defined above,with a dehydrohalogenating agent in an organic solvent and hydrolyzing aresulting methylene compound having a formula (VI): ##STR59## wherein R²is the same as defined above, with a strong alkaline in water or anorganic solvent containing water.